tbuckley/cabot-search huggingface dataset:
Prenatal Lipopolysaccharides Exposure Induces Transgenerational Inheritance of Hypertension
Authors: Nian Cao, Cong Lan, Caiyu Chen, Zaicheng Xu, Hao Luo, Shuo Zheng, Xue Gong, Hongmei Ren, Zhuxin Li, Shuang Qu, Cheng Yu, Jining Yang, Pedro A. Jose, Yundai Chen, Gengze Wu, Cuimei Hu, Junyi Yu, Chunyu Zeng
Journal: Circulation (2022)

Adverse environmental exposure during the prenatal period can lead to diseases in the offspring, including hypertension. Whether or not the hypertensive phenotype can be transgenerationally transmitted is not known.Pregnant Sprague Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) on gestation days 6, 8, 10, and 12 to generate the prenatal LPS exposure model. Blood pressure was monitored by both telemetry and tail-cuff method. RNA sequencing was performed to analyze transcriptome alteration in the kidney of the third generation. Tempol and spironolactone were used to test the potential preventative and therapeutic effect of targeting reactive oxygen species and mineralocorticoid receptor signaling, respectively. Molecular biological experiments were performed to illustrate the mechanism of epigenetic and transcription regulation.Prenatal LPS exposure can impair the ability to excrete a salt load and induce hypertension from the first to the third generations, with the fourth and fifth generations, inducing salt-sensitive hypertension. Compared with control pups, the transcriptome in the kidney of the hypertensive third-generation prenatal LPS-exposed offspring have upregulation of the Ras-related C3 botulinum toxin substrate 1 (Rac1) gene and activation of mineralocorticoid receptor signaling. Furthermore, we found that LPS exposure during pregnancy triggered oxidative stress that upregulated KDM3B (histone lysine demethylase 3B) in the oocytes of first-generation female rats, leading to an inheritable low level of H3K9me2 (histone H3 lysine 9 dimethylation), resulting in the transgenerational upregulation of Rac1. Based on these findings, we treated the LPS-exposed pregnant rats with the reactive oxygen species scavenger, tempol, which successfully prevented hypertension in the first-generation offspring and the transgenerational inheritance of hypertension.These findings show that adverse prenatal exposure induces transgenerational hypertension through an epigenetic-regulated mechanism and identify potentially preventive and therapeutic strategies for hypertension.
Death During Jogging or Running
Authors: Paul D. Thompson
Journal: JAMA (1979)

We investigated the circumstances of death and the medical and activity histories of 18 individuals who died during or immediately after jogging. Thirteen men died of coronary heart disease (CHD) and four men and one woman died of other causes. Six CHD subjects had medical histories relevant to the cardiovascular system, but only one had diagnosed CHD. Six CHD subjects experienced prodromal symptoms but continued vigorous exercise programs. Two subjects had exercised less than a month, but most had trained regularly for years. The CHD risk factors for the CHD cases did not differ significantly from those for other age-matched, physically active men. Superior physical fitness does not guarantee protection against exercise deaths. Physicians and exercising adults should be aware of this fact and give appropriate attention to possible prodromal symptoms. (<i>JAMA</i>242:1265-1267, 1979)
Personalized neoantigen vaccine NEO-PV-01 with chemotherapy and anti-PD-1 as first-line treatment for non-squamous non-small cell lung cancer
Authors: Mark M. Awad, Ramaswamy Govindan, Kristen N. Balogh, David R. Spigel, Edward B. Garon, Meghan E. Bushway, Asaf Poran, Joong Hyuk Sheen, Victoria Kohler, Ekaterina Esaulova, John Srouji, Suchitra Ramesh, Rohit Vyasamneni, Binisha Karki, Tracey E. Sciuto, Himanshu Sethi, Jesse Z. Dong, Melissa A. Moles, Kelledy Manson, Michael S. Rooney, Zakaria S. Khondker, Mark DeMario, Richard B. Gaynor, Lakshmi Srinivasan
Journal: Cancer Cell (2022)
Induction of tumor cell autosis by myxoma virus-infected CAR-T and TCR-T cells to overcome primary and acquired resistance
Authors: Ningbo Zheng, Jing Fang, Gang Xue, Ziyu Wang, Xiaoyin Li, Mengshi Zhou, Guangxu Jin, Masmudur M. Rahman, Grant McFadden, Yong Lu
Journal: Cancer Cell (2022)
Divergent roles for the gut intraepithelial lymphocyte GLP-1R in control of metabolism, microbiota, and T cell-induced inflammation
Authors: Chi Kin Wong, Bernardo Yusta, Jacqueline A. Koehler, Laurie L. Baggio, Brent A. McLean, Dianne Matthews, Randy J. Seeley, Daniel J. Drucker
Journal: Cell Metabolism (2022)
An integrative machine-learning meta-analysis of high-throughput omics data identifies age-specific hallmarks of Alzheimer’s disease
Authors: Maxim N Shokhirev, Adiv A Johnson
Journal: Ageing Research Reviews (2022)

Alzheimer's disease (AD) is an incredibly complex and presently incurable age-related brain disorder. To better understand this debilitating disease, we collated and performed a meta-analysis on publicly available RNA-Seq, microarray, proteomics, and microRNA samples derived from AD patients and non-AD controls. 4089 samples originating from brain tissues and blood remained after applying quality filters. Since disease progression in AD correlates with age, we stratified this large dataset into three different age groups: < 75 years, 75-84 years, and ≥ 85 years. The RNA-Seq, microarray, and proteomics datasets were then combined into different integrated datasets. Ensemble machine learning was employed to identify genes and proteins that can accurately classify samples as either AD or control. These predictive inputs were then subjected to network-based enrichment analyses. The ability of genes/proteins associated with different pathways in the Molecular Signatures Database to diagnose AD was also tested. We separately identified microRNAs that can be used to make an AD diagnosis and subjected the predicted gene targets of the most predictive microRNAs to an enrichment analysis. The following key themes emerged from our machine learning and bioinformatics analyses: cell death, cellular senescence, energy metabolism, genomic integrity, glia, immune system, metal ion homeostasis, oxidative stress, proteostasis, and synaptic function. Many of the results demonstrated unique age-specificity. For example, terms highlighting cellular senescence only emerged in the earliest and intermediate age ranges while the majority of results relevant to cell death appeared in the youngest patients. Existing literature corroborates the importance of these hallmarks in AD.
Vaccine subtype and dose interval determine immunogenicity of primary series COVID-19 vaccines in older people
Authors: Helen Parry, Rachel Bruton, Reni Ayodele, Penny Sylla, Graham McIlroy, Nicola Logan, Sam Scott, Sam Nicol, Kriti Verma, Christine Stephens, Brian Willett, Jianmin Zuo, Paul Moss
Journal: Cell Reports Medicine (2022)

Age is the strongest determinant of COVID-19 mortality, and over 2 billion people have received primary series vaccination with BNT162b2 (mRNA) or ChAdOx1 (adenoviral vector). However, the profile of sustained vaccine immunogenicity in older people is unknown. Here, we determine spike-specific humoral and cellular immunity to 8 months following BNT162b2 or ChAdOx1 in 245 people aged 80–98 years. Vaccines are strongly immunogenic, with antibodies retained in every donor, while titers fall to 23%–26% from peak. Peak immunity develops rapidly with standard interval BNT162b2, although antibody titers are enhanced 3.7-fold with extended interval. Neutralization of ancestral variants is superior following BNT162b2, while neutralization of Omicron is broadly negative. Conversely, cellular responses are stronger following ChAdOx1 and are retained to 33%–60% of peak with all vaccines. BNT162b2 and ChAdOx1 elicit strong, but differential, sustained immunogenicity in older people. These data provide a baseline to assess optimal booster regimen in this vulnerable age group.
Residential Wood Burning and Pulmonary Function in the Agricultural Lung Health Study
Authors: Julie D. White, Annah B. Wyss, Thanh T. Hoang, Mikyeong Lee, Marie Richards, Christine G. Parks, Laura E. Beane-Freeman, John L. Hankinson, David M. Umbach, Stephanie J. London
Journal: Environmental Health Perspectives (2022)

Background: In low- and middle-income countries, burning biomass indoors for cooking or heating has been associated with poorer lung function. In high-income countries, wood, a form of biomass, is commonly used for heating in rural areas with increasing prevalence. However, in these settings the potential impact of chronic indoor woodsmoke exposure on pulmonary function is little studied. Objective: We evaluated the association of residential wood burning with pulmonary function in case–control study of asthma nested within a U.S. rural cohort. Methods: Using sample weighted multivariable linear regression, we estimated associations between some and frequent wood burning, both relative to no exposure, in relation to forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), their ratio (FEV1/FVC), and fractional exhaled nitric oxide (FeNO). We examined effect modification by smoking or asthma status. Results: Among all participants and within smoking groups, wood burning was not appreciably related to pulmonary function. However, in individuals with asthma (n=1,083), frequent wood burning was significantly associated with lower FEV1 [β: −164mL; 95% confidence interval (CI): −261, −66mL], FVC (β: −125mL; 95% CI: −230, −20mL), and FEV1/FVC (β: −2%; 95% CI: −4, −0.4%), whereas no appreciable association was seen in individuals without asthma (n=1,732). These differences in association by asthma were statistically significant for FEV1 (pinteraction=0.0044) and FEV1/FVC (pinteraction=0.049). Frequent wood burning was also associated with higher FeNO levels in all individuals (n=2,598; β: 0.1 ln(ppb); 95% CI: 0.02, 0.2), but associations did not differ by asthma or smoking status. Discussion: Frequent exposure to residential wood burning was associated with a measure of airway inflammation (FeNO) among all individuals and with lower pulmonary function among individuals with asthma. This group may wish to reduce wood burning or consider using air filtration devices. https://doi.org/10.1289/EHP10734
Letter to the Editor: Metabolic dysfunction‐associated fatty liver disease and excessive alcohol consumption are both independent risk factors for mortality
Authors: Hong‐Xia Li, Zhi‐Qin Xie, Zhao‐Ming Yang, Cai‐Xi Tang
Journal: Hepatology (2022)

To the editor, We read the study by van Kleef et al.,1 which investigated the mortality risk of patients with metabolic‐associated fatty liver disease (MAFLD) in relation to alcohol use. The authors concluded that MAFLD increased mortality risk independent of excessive alcohol consumption. However, we have some concerns about this conclusion. First, a previous study has investigated the association between MAFLD and all‐cause mortality.2 They included 7761 individuals who fasted for >8 h, whereas 13,225 participants with available alcohol and liver ultrasound data were included in this study. The current study cohort had higher prevalence of MAFLD (34.7% vs. 25.9%) at baseline than the previously reported study. Considering that diabetes was an important diagnostic parameter defined by fasting glucose levels, we believe that the inclusion of an 8‐h fasting blood glucose level adds further credibility to the results and conclusions.3 Second, it is known that National Health and Nutrition Examination Survey recommends sampling weights to represent a nationally representative sample of the US population. Regretfully, any sampling weights were not used in the presented data. Of note, inverse probability treatment weighting (IPTW) is an efficient and reliable approach to address imbalances. Because the authors chose IPTW to minimize the potential bias in this study, details were not shown before and after IPTW, such as the baseline table and the Cox regression analysis. Thus, more details are suggested. Third, some important metabolic cofactors were not adjusted in multivariate analysis, such as diabetes, hypertension, and cholesterol levels. Metabolic factors were important confounders in the study of MAFLD, which also needed to be adjusted in the multivariable adjusted analysis.2 However, as shown in Tables 3 and 4 of van Kleef et al., metabolic factors were not adjusted in the multivariable adjusted analysis. Therefore, the findings that MAFLD and excessive alcohol were independent and simultaneous predictors for all‐cause mortality might be inadequate. Our confusion is regarding whether their prognosis in MAFLD−Alc+ group was not determined by simply alcohol consumption but rather by alcohol‐related metabolic disorders leading to health concerns.4 For this reason, we recommend that confounders of metabolic factors should be considered in this study. In summary, consideration about the mentioned questions may help solidify the conclusions of this study.
Letter to the editor: Targeted decrease of portal hepatic pressure gradient improves ascites control after TIPS
Authors: Wenhao Luo, Yawen Wang, Ye Li, Taiping Zhang
Journal: Hepatology (2022)

To the editor, We read the study by Queck et al., which showed that extend of portal hepatic pressure gradient (PPG) reduction and/or lowering of target PPG immediately after transjugular intrahepatic portosystemic shunt insertion (TIPS) placement is associated with improved short‐term ascites control and long‐term survival.1 However, we have some concerns about this conclusion. First, there are significant differences in the baseline characteristics of patients. Although the authors adjusted several factors in the multivariable‐adjusted analysis (Child‐Pugh score, white blood cell count, and sodium), some important factors affecting ascites control and survival were not included, such as age, serum ammonia, albumin, bilirubin, creatinine, etiology of liver disease, and International Normalized Ratio.2,3 In particular, a recent study demonstrated that age, albumin, and model for end‐stage liver disease PPG score were associated with mortality in patients with ascites.4 Furthermore, patients with ascites with portal hypertension and hypoproteinemia were reported to have liver dysfunction. Thus, weaker liver function at baseline was an important confounding factor in the study. Therefore, baseline imbalances among the factors closely associated with the outcomes may lead to deviations in estimating the effects. Second, the exclusion criteria in the study were not appropriate, such as bilirubinemia >7 mg/dl, which is not the absolute contraindication of TIPS. The intended exclusion of patients with more severe ascites may tend to achieve subjective survival outcomes. Moreover, it is unclear whether the study chose covered TIPS or uncovered TIPS. Previous studies have shown that uncovered TIPS is closely related to the occurrence of hepatic encephalopathy, which leads to higher mortality.3 Third, patients with liver cirrhosis may be subject to more medical and lifestyle monitoring after initial diagnosis. PPG decreases spontaneously over time, especially in the medical and lifestyle monitoring.5 The dynamic change of baseline characteristics will influence the research results. Meanwhile, in this study, baseline PPG varies widely, which leads to different PPG reduction range from the baseline. Finally, the specific level of ascites of included patients was not further subdivided. A recent study showed that the prognosis of patients with different ascites grades seems completely different.4 In conclusion, whether PPG reduction after TIPS is associated with ascites control or better survival remains challenging.
Nicotine exacerbates endothelial dysfunction and drives atherosclerosis via extracellular vesicle-miRNA
Authors: Chao Wang, Cong Liu, Jiaxin Shi, Hairu Li, Shuangquan Jiang, Peng Zhao, Maomao Zhang, Guoqing Du, Shuai Fu, Shouqiang Li, Zhuo Wang, Xiaokun Wang, Fei Gao, Ping Sun, Jiawei Tian
Journal: Cardiovascular Research (2022)

Abstract Aims Nicotine, a major component of tobacco, is an important factor contributing to atherosclerosis. However, the molecular mechanisms underlying the link between nicotine and atherosclerosis are unclear. As extracellular vesicles (EVs) are involved in intercellular communication in atherosclerosis, we investigated whether their influence on arterial pathophysiology under nicotine stimulation. Methods and results EVs from the serum of smokers (smoker-EVs) were significantly increased and exacerbated endothelial inflammation, as well as apoptosis according to functional studies. Meanwhile, inhibition of EVs blunted the nicotine-induced atherosclerosis progression, and injection of nicotine-induced EVs promoted atherosclerosis progression in ApoE–/– mice. Furthermore, quantitative reverse transcription-polymerase chain reaction analysis revealed a remarkable increase in miR-155 levels in smoker-EVs, which was correlated with carotid plaque formation in patients measured by ultrasound imaging. Moreover, CD14 levels were significantly increased in EVs from smokers (representing EVs derived from monocytes), indicating that monocytes are an important source of smoker-EVs. DNA methylation and the transcription factor HIF1α may contribute to increased miR-155 levels in monocytes, as assessed with bisulfite conversion sequencing and chromatin immunoprecipitation. Mechanistically, EVs encapsulated miR-155 induced endothelial cell dysfunction by directedly targeting BCL2, MCL1, TIMP3, BCL6, and activating NF-κB pathway, as verified in a series of molecular and biological experiments. Injecting EVs from nicotine-stimulated monocytes promoted plaque formation and triggered vascular endothelial injury in ApoE–/– mice, whereas inhibition of miR-155 weakened this effect. Conclusion Our findings revealed an EV-dependent mechanism of nicotine-aggravated atherosclerosis. Accordingly, we propose an EV-based intervention strategy for atherosclerosis management.
The Genetic Echo of the Tarim Mummies in Modern Central Asians
Authors: Shan-Shan Dai, Xierzhatijiang Sulaiman, Jainagul Isakova, Wei-Fang Xu, Najmudinov Tojiddin Abdulloevich, Manilova Elena Afanasevna, Khudoidodov Behruz Ibrohimovich, Xi Chen, Wei-Kang Yang, Ming-Shan Wang, Quan-Kuan Shen, Xing-Yan Yang, Yong-Gang Yao, Almaz A Aldashev, Abdusattor Saidov, Wei Chen, Lu-Feng Cheng, Min-Sheng Peng, Ya-Ping Zhang
Journal: Molecular Biology and Evolution (2022)

Abstract The diversity of Central Asians has been shaped by multiple migrations and cultural diffusion. Although ancient DNA studies have revealed the demographic changes of the Central Asian since the Bronze Age, the contribution of the ancient populations to the modern Central Asian remains opaque. Herein, we performed high-coverage sequencing of 131 whole genomes of Indo-European-speaking Tajik and Turkic-speaking Kyrgyz populations to explore their genomic diversity and admixture history. By integrating the ancient DNA data, we revealed more details of the origins and admixture history of Central Asians. We found that the major ancestry of present-day Tajik populations can be traced back to the admixture of the Bronze Age Bactria–Margiana Archaeological Complex and Andronovo-related populations. Highland Tajik populations further received additional gene flow from the Tarim mummies, an isolated ancient North Eurasian–related population. The West Eurasian ancestry of Kyrgyz is mainly derived from Historical Era populations in Xinjiang of China. Furthermore, the recent admixture signals detected in both Tajik and Kyrgyz are ascribed to the expansions of Eastern Steppe nomadic pastoralists during the Historical Era.
Current status and future perspectives in targeted therapy of NPM1-mutated AML
Authors: Roberta Ranieri, Giulia Pianigiani, Sofia Sciabolacci, Vincenzo Maria Perriello, Andrea Marra, Valeria Cardinali, Sara Pierangeli, Francesca Milano, Ilaria Gionfriddo, Lorenzo Brunetti, Maria Paola Martelli, Brunangelo Falini
Journal: Leukemia (2022)

Abstract Nucleophosmin 1 (NPM1) is a nucleus-cytoplasmic shuttling protein which is predominantly located in the nucleolus and exerts multiple functions, including regulation of centrosome duplication, ribosome biogenesis and export, histone assembly, maintenance of genomic stability and response to nucleolar stress. NPM1 mutations are the most common genetic alteration in acute myeloid leukemia (AML), detected in about 30–35% of adult AML and more than 50% of AML with normal karyotype. Because of its peculiar molecular and clinico-pathological features, including aberrant cytoplasmic dislocation of the NPM1 mutant and wild-type proteins, lack of involvement in driving clonal hematopoiesis, mutual exclusion with recurrent cytogenetic abnormalities, association with unique gene expression and micro-RNA profiles and high stability at relapse, NPM1 -mutated AML is regarded as a distinct genetic entity in the World Health Organization (WHO) classification of hematopoietic malignancies. Starting from the structure and functions of NPM1, we provide an overview of the potential targeted therapies against NPM1 -mutated AML and discuss strategies aimed at interfering with the oligomerization (compound NSC348884) and the abnormal traffic of NPM1 (avrainvillamide, XPO1 inhibitors) as well as at inducing selective NPM1-mutant protein degradation (ATRA/ATO, deguelin, (-)-epigallocatechin-3-gallate, imidazoquinoxaline derivatives) and at targeting the integrity of nucleolar structure (actinomycin D). We also discuss the current therapeutic results obtained in NPM1 -mutated AML with the BCL-2 inhibitor venetoclax and the preliminary clinical results using menin inhibitors targeting HOX/MEIS1 expression. Finally, we review various immunotherapeutic approaches in NPM1 -mutated AML, including immune check-point inhibitors, CAR and TCR T-cell-based therapies against neoantigens created by the NPM1 mutations.
Prosthesis-Patient Mismatch Affects Survival After Aortic Valve Replacement
Authors: Vivek Rao, W. R. Eric Jamieson, Joan Ivanov, Susan Armstrong, Tirone E. David
Journal: Circulation (2000)

Background —Surgeons traditionally avoid the use of “small” aortic prostheses because of the potential for residual left ventricular outflow tract obstruction and persistent transvalvular gradients. This study examines the ratio between prosthetic valve size and the body surface area (BSA) of patients undergoing aortic valve replacement (AVR). We sought to determine the effect of potential “prosthesis-patient” mismatch on long-term survival. Methods and Results —Follow-up was conducted on 2981 patients who underwent AVR with stented bioprostheses between 1976 and 1996. To account for differences between manufacturers’ labeled valve sizes, we calculated the ratio between the prosthetic valve effective orifice area (EOA) and the patient’s BSA (recorded for 2154 patients). The lowest decile in this cohort had a calculated EOA/BSA of &lt;0.75 cm 2 /m 2 (Small group, n=227) compared with the control group (n=1927), in whom the EOA/BSA ratio was &gt;0.75 cm 2 /m 2 . Operative mortality was higher in the Small group (8% versus 5%, P =0.03). Actuarial survival at 12 years was 50±5% in the Small group compared with 49±2% in the control group ( P =0.27). However, freedom from valve-related mortality was significantly lower in the Small group (75±5% versus 84±2%, P =0.004). Cox regression analysis determined age and NYHA functional class to be the multivariate predictors of overall mortality, whereas advanced age and EOA/BSA &lt;0.75 cm 2 /m 2 were found to be the predictors of valve-related mortality. Conclusions —Prosthesis-patient mismatch results in significantly higher early and late mortality after bioprosthetic AVR. We recommend careful selection of stented bioprostheses to ensure an adequate ratio of EOA to BSA. An EOA/BSA ratio of &gt;0.75 cm 2 /m 2 may avoid residual left ventricular outflow tract obstruction and persistent transvalvular gradients. Careful prosthesis-patient matching will improve both early and late survival after AVR.